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They are embedded in the cell membrane

Origin of Angiosperms

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Each one ofthese struggles is hypothesized as being biased, although not settledoutright, by a top-down attention-specific signal (Desimone andDuncan, 1995, Reynolds and Desimone, 2001).We have said that competitions are selective in ways that do notinvolve limitations in capacity, and that competition-based theoriesof attention’s underlying mechanisms are therefore naturalaccompaniments to selection-for-action type views of attention’sfunction (Section ), and perhaps of other views that involve a break from the Broadbentianview, according to which the function of attention is the managementof capacity limitations.

Aquaporin proteins are composed of a bundle of six transmembrane α-helices

The rigid ligands used here were developed as D1 agonists but were previously shown also to be functionally selective D2 ligands both in heterologous systems (; ) and in situ (; ). They have atypical behavioral properties expected of canonical D1:D2 agonists (; ; ). Thus, these ligands provide useful probes for our studies, and resulting hypotheses may explain novel actions of these compounds in vivo.

319 | Peiwen Wu, Yang Yu, Claire E

For these studies, we compared the actions of the endogenous ligand dopamine and the prototypical D2 agonist quinpirole with those of DHX, DNS, and DNX. The D2 functional selectivity of dihydrexidine in vitro is consistent with both its D2 functional selectivity in situ (; ) and its lack of amphetamine-like behavioral actions (), despite being a full D1 and D2 agonist at the canonical signaling pathway. Of particular importance for the present study is the fact that dihydrexidine has a fused ring structure with no rotatable bonds. This relatively rigid structure decreases the degrees of freedom in interpreting data of the type this study was designed to generate. The second important ligand used was dinapsoline, another rigid compound that also has been shown to have functionally selective properties with the D2 wild-type receptor (). The third related ligand was dinoxyline, a compound that differs from dinapsoline only in an ether-methylene bridge substitution, a feature hypothesized to influence receptor interactions in subtle, but meaningful, ways. The structures of the eutomers of these compounds are shown in . In all cases, the D2 affinity of the distomer is at least 100-fold less than the eutomer at the wild-type D2 receptor, and because of limited or unavailability of pure eutomer, racemic mixtures were used for this research. The reported K0.5 values are based on the concentration of the racemate and were not corrected for the effects of the distomer. The synthetic ligands had no functional effect in any of these assays performed in wild-type CHO K1 cells not containing the D2L receptor. The D2 antagonist domperidone (10 μM) was tested against WT and all receptor mutants; as expected, no functional activation was seen at any endpoint tested. Domperidone completely blocked quinpirole activation of all effector endpoints with both WT and mutant receptors.

Antagonists were essentially unaffected by these TM5 serine mutations because their binding to the D2 receptor, unlike that of agonists, is less dependent on interactions with these residues. The effects on the binding of these agonist ligands also were largely predictable by existing molecular models, whereas these mutations caused patterns of effects on the functional activity of the probe ligands not directly predictable from binding. One hypothesis is that ligands can cause receptor populations to shift between groups of discrete active states that are linked to specific signaling pathways. Alternatively, each ligand may induce a discrete range of conformational changes that affect, in a graded fashion, whether specific signaling pathways are activated. At present, the former hypothesis is one that has been largely favored and is the one that would explain the constitutive activity often seen in cellular systems. In any event, the ability to form and test hypotheses about how such changes occur can be heuristically interesting but also may lead to structure-based discovery of novel functionally selective ligands.

Cytochrome P450 enzymes in drug metabolism: Regulation …

In the current study, computational approaches were used to hypothesize specific binding interactions within each ligand-receptor complex. The affinity and functional properties of the probe and reference ligands was then assessed using four distinct functional endpoints. The resulting data are consistent with the hypothesis that subtle changes in ligand-specific interactions induced by mutation of selected amino acids of the receptor may stabilize and/or induce certain receptor conformations that lead to functional selectivity (i.e., differential activation of one or more signaling pathways).

Functional selectivity is the term that describes drugs that cause markedly different signaling through a single receptor (e.g., full agonist at one pathway and antagonist at a second). It has been widely recognized recently that this phenomenon impacts the understanding of mechanism of action of some drugs, and has relevance to drug discovery. One of the clinical areas where this mechanism has particular importance is in the treatment of schizophrenia. Antipsychotic drugs have been grouped according to both pattern of clinical action and mechanism of action. The original antipsychotic drugs such as chlorpromazine and haloperidol have been called typical or first generation. They cause both antipsychotic actions and many side effects (extrapyramidal and endocrine) that are ascribed to their high affinity dopamine D2 receptor antagonism. Drugs such as clozapine, olanzapine, risperidone and others were then developed that avoided the neurological side effects (atypical or second generation antipsychotics). These compounds are divided mechanistically into those that are high affinity D2 and 5-HT2A antagonists, and those that also bind with modest affinity to D2, 5-HT2A, and many other neuroreceptors. There is one approved third generation drug, aripiprazole, whose actions have been ascribed alternately to either D2 partial agonism or D2 functional selectivity. Although partial agonism has been the more widely accepted mechanism, the available data are inconsistent with this mechanism. Conversely, the D2 functional selectivity hypothesis can accommodate all current data for aripiprazole, and also impacts on discovery compounds that are not pure D2 antagonists.

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  • Inorganics | An Open Access Journal from MDPI

    Aquaporin - Wikipedia

  • Inorganics, an international, peer-reviewed Open Access journal.

    COX-3 - Wikipedia

  • Title: Functional Selectivity in Cannabinoid Signaling

    COX-3 is an enzyme that is encoded by the PTGS1 (COX1) gene, but is not functional in humans

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Functional selectivity - an overview | ScienceDirect Topics

Subtle structural difference in a ligand may lead to functional selectivity (; ). Thus, we hypothesized that modification of the D2L receptor in regions where such ligands bind could be informative about the manner by which functionally selective signaling occurs. The current experiments address this hypothesis by studying the role of specific binding interactions that occur between the D2L receptor and three rigid analogs, dihydrexidine (DHX) (), DNS (), and DNX (). These ligands were originally designed as novel D1 agonists in which the accessory phenyl ring was expected to confer both high D1 affinity and high D1:D2 selectivity (; ; ). All three compounds also unexpectedly had significant D2 affinity, leading to the discovery of D2 functionally selective signaling for DHX and DNS (; ; ).

To test compounds for functional selectivity, ..

For some time, the overall implications of functional selectivity to drug action in vivo was not widely accepted despite some of the available data. For example, classic pharmacology would have predicted that a compound with full intrinsic activity at both D1 and D2 receptors (i.e., dihydrexidine at both D1 and D2 receptors modulating adenylate cyclase) would have behavioral effects similar to apomorphine or amphetamine, direct or indirect activators of both families of receptor. Clearly, however, dihydrexidine did not have the expected behavioral actions of a mixed D1:D2 agonist []. This was consistent with the hypothesis that the atypical D2 signaling properties of the this compound markedly affected its pharmacological actions in vivo.

GPCR functional selectivity has therapeutic impact: …

Design, Synthesis, and Evaluation of Novel COX-2 Inhibitors
Cyclooxygenase-2 (COX-2) is the molecular target of non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors. Our laboratory has combined structural analysis with functional studies to define the molecular determinants of the interaction of ligands (substrates and inhibitors) with COX-2. For example, we recently reported the identification of a critical H-bonding interaction that leads to the selectivity of aspirin for acetylation of Ser-530 in COX-2. Many NSAIDs are aralkyl carboxylic acids. Comparative analysis of the effect of site-directed mutation of active site residues on the binding of substrates and inhibitors to COX-1 and COX-2 led us to hypothesize that neutral derivatives of esters and amides would bind selectively to COX-2. We tested this hypothesis by synthesizing a series of neutral derivatives of NSAIDs and demonstrating increases in selectivity for COX-2 of several orders of magnitude. We are exploiting this discovery to prepare novel COX-2 inhibitors as anti-inflammatory drugs and cancer preventive agents.

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